ReviewFrontiers in immunology2026
Targeting Tumour Heterogeneity through sequential timing of anti-hallmark combination therapies -a hypothesis for implementation.
Review in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Since the introduction of the hallmarks of cancer framework over 25 years ago, treatment approaches have evolved into personalized medicine, offering benefits to select patient populations. However, three major components of heterotypic interactions in cancer-mutational evolution of cancer stem cells, epithelial-mesenchymal plasticity (EMP), and cancer-remodeled extracellular matrix (ECM)-remain critical barriers to therapy, particularly in patients who have failed treatment. EMP encompasses a spectrum of to-and-fro transitions between mesenchymal and epithelial states, yielding hybrid phenotypes of evolutionary heterogeneity. These are embedded in the vascular, metabolic, mutational, and immune-suppressive reprogramming of the tumor microenvironment (TME), induced and advanced by the hypoxia-reactive oxygen species (ROS)-hypoxia-inducible factor-1α (HIF-1α)-transforming growth factor-β (TGF-β) signaling axis. This review systematically examines the molecular mechanisms underlying EMP, tumor heterogeneity, and the hallmarks of cancer. It explores pharmacological strategies to target tumor burden, epigenetically revert transitional states, and restore immune-editing functions. Based on this analysis, we propose a phased anti-hallmark Combinations, Timing, and Sequencing (CTS) protocol. The methodology integrates vascular normalization, epigenetic modifiers, trimodal radiotherapy or stereotactic body radiotherapy (SBRT), chemotherapy (CT), and immunotherapy optimization, aiming to improve outcomes while minimizing toxicities. Also, mechanistically, by reverting mesenchymal phenotypes and normalizing the vasculature, the CTS protocol is designed to rescue the immune-suppressive tumor microenvironment-curtailing the recruitment of myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells. This restores cytotoxic T-cell homing, thereby converting immunologically "cold" tumors into "hot," immunotherapy-responsive lesions.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.